Angelman syndrome (AS) is an infrequent, unusual autosomal neuro-developmental disease resulting from epigenetic sex-specific genomic imprinting and uniparental disomy of paternal chromosome 15 with a simultaneous functional loss of the maternal part 15q11-q13. With a focus on clinical, diagnostic and management aspects, this article encompasses a detailed discussion on the genetic mechanisms involved in AS.

00:00
Angelman syndrome though is a completely different expression because it results from a microdeletionon the maternal chromosome. Let’s look at the schematic again. Both parents have both chromosomes.
00:14
However, on the maternal chromosome, we see that the Angelman syndrome region, the red region is expressed.
00:23
However, on the paternal chromosome, that region is imprinted, meaning that it is turned offand hypermethylated, so imprinting turned off. Now, if the maternal chromosome has a microdeletionthat spans that region of chromosome 15, then she does not have the Angelman syndrome genesexpressed or it does not have the Angelman gene syndrome expressed. Thus, the individual has no genesexpressed in that Angelman syndrome region of chromosome 15 and they develop Angelman syndrome.
01:04
Angelman syndrome is an image on the right side of the screen here of what an individuallooks like and here are a few more. Let’s take a look at some of the phenotypic features of Angelman.
01:19
Again, you’ll see they’re quite distinct from those that we see in Prader-Willi syndrome even thoughthe deletion is in the same region of the gene. Angelman is one of the researchers that identified this gene.
01:35
But prior to his time, this syndrome was known as the happy puppet syndrome. It might help youremember the symptoms of Angelman because these children tend to smile and giggle a lot.
01:51
They’re ever so happy although fairly severely intellectually disabled. They also have pretty jerky movementsas well as short stature and they often exhibit seizures. They don’t talk a whole lot. Often, there aredevelopmental delays. The intellectual disabilities are much more severe than you see in Prader-Willi.
02:19
Another feature is that they often have fairly widely-spaced teeth. But in general for me in remembering it,we have the happy puppet as Angelman and then a serious need for food in Prader-Willi syndrome.
02:35
Those would be the overall big features to remember to keep these syndromes in mind.
02:41
Now, Prader-Willi and Angelman syndrome are mostly derived from these deletions in the Q armof chromosome 15. Specifically, you can see the megabase numbers but that’s not really somethingso important for you to remember. I’m going to introduce a whole another concept here.
03:06
Some of the rest of these conditions come from a uniparental disomy. If you have, in this case,two maternal chromosomes that both have the Prader-Willi region hypermethylated,then they would have no Prader-Willi gene product and thus develop Prader-Willi syndrome.
03:31
Less of the time, we see Angelman syndrome derived from a paternal uniparental disomy.
03:42
We’ll look at how this happens in just a moment. Because both of those chromosomesare hypermethylated in the Angelman syndrome region, they would develop Angelman syndrome.
03:54
So what is uniparental disomy and how do we even get there? It sounds like a pretty strange term.
04:01
Let’s take a look at meiosis again. Here, we have two chromosomes. We’re going to go throughtheir homologous pair. Let’s say we have nondisjunction during meiosis I. Then the next division,meiosis II, we see that each resulting oocyte is disomic, meaning it’s got both copies. In this case,we’ll go with the chromosome 15. The sperm comes along and fertilizes the egg. Now, it’s triploid.
04:35
But one thing that can happen that I mentioned in a previous lecture is you can have a trisomy rescuewhere the resulting zygote recognizes that it has three copies of this chromosome and kicks one out.
04:53
So now, we have a zygote that has two chromosomes but both of them are from maternal originin this situation. This can happen in another way. Here, it’s called heterodisomy where we have themboth from one parent. Now, let’s look at isodisomy. Let’s say meiosis I happens fine but meiosis IIdoesn’t happen quite the way it should. We have nondisjunction of the sister chromatids resultingin a disomic ovum which then could be fertilized by a sperm that either doesn’t have a chromosomebecause it had nondisjunction of its own or it could have a chromosome that is also rejectedin trisomy rescue. Either way, we have two chromosomes that are from the same egg in this situation,right and so isodisomy. Heterodisomy, we have two different chromosomes. I think I misspoke.
06:08
Heterodisomy, we have two different chromosomes from the same parent. Isodisomy, we have twoof exactly the same chromosome, so sister chromatids, exact copies of each other, isodisomy.
06:21
So disomy, two chromosomes, one parent; iso, both of them are exactly the same.
06:28
So again, although this is uncommon, I bring this up so that you can understand the conceptof uniparental disomy and how it might manifest itself in certain genetic conditions.
06:41
As I bring this lecture to a close, I look forward to seeing you in the next lecturewhere we have some really exciting conditions looking at these sex chromosomes.

About the Lecture

The lecture Angelman Syndrome by Georgina Cornwall, PhD is from the course Chromosomal Disorders.

Included Quiz Questions

What is the cause of Angelman Syndrome?

A microdeletion in maternal chromosome 15

A microdeletion in paternal chromosome 15

A microdeletion in maternal chromosome X

A microdeletion in maternal chromosome Y

A microdeletion in paternal chromosome X

Which of the following is NOT a phenotypic feature of Angelman Syndrome?

Hyperphagia

Microcephaly

Short stature

Frequent smiling

Frequent laughing

What is another term for "Angelman Syndrome"?

Happy Puppet Syndrome

Happy Feet Syndrome

Hungry Puppet Syndrome

Serious Food Syndrome

Serious Puppet Syndrome

How is heterodisomy most likely to occur?

Non-disjunction in meiosis I and trisomy rescue after fertilization with a normal sperm

Non-disjunction in meiosis II and trisomy rescue after fertilization with a normal sperm

Non-disjunction in meiosis II and trisomy rescue after fertilization with a sperm that does not contain that chromosome

Non-disjunction in meiosis II and fertilization with a sperm that does not contain that chromosome

Non-disjunction in meiosis I and trisomy rescue after fertilization with a sperm that does not contain that chromosome

Which of the following is true for a zygote formed through isodisomy?

Two chromosomes are inherited from one parent and are exact copies of each other.

Two chromosomes are inherited from one parent and are different from each other.

Two chromosomes are inherited from both parents and are exact copies of each other.

Two chromosomes are inherited from both parent and are not exact copies of each other.

Two chromosomes are inherited from one parent and are similar but not exact copies of each other.

Author of lecture Angelman Syndrome

Georgina Cornwall, PhD

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